Protected Indazole Boronic Acid Pinacolyl Esters

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successful method developed in our laboratory.16 Then, it was required to ..... (3) (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019. ..... 2001, 11, 1153. (30) The use of Oxone® (2KHSO5–KHSO4–K2SO4) as oxidative.
LETTER

615

Protected Indazole Boronic Acid Pinacolyl Esters: Facile Syntheses and Studies of Reactivities in Suzuki–Miyaura Cross-Coupling and Hydroxydeboronation Reactions ReactivtiesinSuz ki–MiyauraCros -Coupling François Crestey, Elodie Lohou, Silvia Stiebing, Valérie Collot,* Sylvain Rault Université de Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Centre d’Études et de Recherche sur le Médicament de Normandie (CERMN), UPRES EA-4258, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen Cedex, France Fax +33(2)31931188; E-mail: [email protected] Received 8 October 2008

Abstract: The paper describes a rapid and efficient synthesis for the isolation of protected indazolylboronic esters. These compounds were synthesized by reaction between prepared protected haloindazoles and bis(pinacolato)diboron. The effects of solvent, temperature, reaction time, and the nature of halogen atom as well as protecting group were investigated. Additionaly, these compounds reacted either with aryl halides in a Suzuki–Miyaura crosscoupling reaction or with hydrogen peroxide in a hydroxydeboronation reaction showing the potential access to new aryl and hydroxyindazole libraries. Key words: indazole boronic acid pinacolyl esters, Suzuki– Miyaura cross-coupling reaction, palladium-mediated reaction, protected halo-1H-indazoles, hydroxydeboronation

Our group has long been interested in the design and synthesis of new polyfunctionalized indazole libraries,1 particularly those derived from the 2-aza bioisosteres of tryptamine, serotonin, melatonin, or tryptophan.2 In the present work we extend the studies on our ongoing research program to the development of a rapid methodology for the synthesis of indazolylboronic esters for the purpose to prepare new valuable building blocks in medicinal chemistry. Boronic acids and esters have emerged as two of the most useful classes of organoboron compounds in organic synthesis, particularly for the formation of carbon–heteroatom bonds3 and in Pd-catalyzed crosscoupling reactions with organic halides and triflates (the Suzuki–Miyaura reaction).4 Moreover, these synthetic intermediates provide a versatile and efficient access to hydroxy,5 halo,6 nitro,7 and keto8 compounds as well as amino acids.9 Furthermore, over the past few years there has been an increased availability of heteroaromatic boronic acids and esters.10,11 In contrast, indazolylboronic acids or esters have been surprisingly poorly investigated, and an exhaustive survey of literature revealed only few articles and patents wherein procedures were not always clearly explained.12–15 With this in mind, we first evaluated the feasibility of the transformation of various haloindazoles III into the corresponding boronates II. Several reaction parameters were

SYNLETT 2009, No. 4, pp 0615–0619xx. 209 Advanced online publication: 16.02.2009 DOI: 10.1055/s-0028-1087922; Art ID: G32908ST © Georg Thieme Verlag Stuttgart · New York

R N

Y

N

X

N

(R'O)2B

N I

R

R

N II

R'

III

R'

N H

X = halogen; R' = protecting group; Y = aryl or OH

Scheme 1

varied, including the nature of protecting group and halogen atom as well as the effects of solvent, temperature, and reaction time. This was followed by a Pd-catalyzed coupling reaction of several freshly prepared boronates showing the reactivity of these functionalized building blocks and a potential access to a promise heterocyclic library I. In addition, we now provide as well an alternative for the synthesis of hydroxyindazoles by hydroxydeboronation (Scheme 1). R

R i or ii or iii

N

X N H 1a–g

X

N N

R = H, Me X = Br, I

R'

R' = SEM 2a–f R' = Ac 3a–e R' = THP 4a–d

Scheme 2 Reagents and conditions: i) SEMCl (1.1 equiv), TBABr (0.01 equiv), CH2Cl2/KOH aq 50%, 0 °C for 1 h then at r.t. for 2 h, 52–99%; ii) Ac2O, reflux conditions, 2 h, 80–100%; iii) DHP (2.5 equiv), TFA (cat), EtOAc, reflux conditions, 6 h, 70–100%.

First, indazoles 1a–g bearing bromo or iodo halogen atoms in position 4, 5, 6, and 7 were prepared from the corresponding 2-alkylanilines according to a previously successful method developed in our laboratory.16 Then, it was required to protect the nitrogen atom of the indazole nucleus at this stage for potential subsequent reactions as well as avoiding possible side reactions during the borylation. Accordingly, the following groups have been used for the protection step: 2-(trimethylsilanyl)ethoxymethyl (SEM), acetyl (Ac) and tetrahydropyran-2-yl (THP). Next, a procedure recently published by Kania and coworkers,17 protection in a biphasic mixture CH2Cl2/KOH (50% solution in H2O) in the presence of SEMCl (1.1 equiv) and a catalytic amount of TBABr, provided 1-SEM1H-haloindazoles 2a–f. Protected indazoles 3a–e were obtained by reaction with acetic anhydride for two hours under reflux conditions with excellent yields. Moreover,

616 Table 1

LETTER

F. Crestey et al. Synthesis of Protected Halo-1H-indazoles 2a–f, 3a–e, and 4a–d from the Corresponding Halo-1H-indazoles 1a–g

Indazoles

X

R

1a

4-Br

H

2a

96

3a

1b

4-I

H

2b

52



1c

5-Br

H

2c

81

1d

5-Br

Me



1e

5-I

H

1f

6-Br

1g

7-Br

a

Yield (%) of 2

Yield (%) of 3

Yield (%) of 4

100

4a

82







3b

92

4b

70a



3c

83





2d

99









H

2e

92

3d

86

4c

H

2f

97

3e

80

4d = 4da/4db (3:1)

100a 76

The reaction was performed in CHCl3.

taking into account the previously described works in pyrazole18 and imidazole series,19 in which THP was an excellent N-protecting group to prepare boronic acid derivatives, haloindazoles 1a,c,f,g reacted with dihydropyran following a standard procedure described by Young and co-workers.20 These conditions provided THP-protected indazoles 4a–d in very good yields. For the compounds 4b,c, chloroform was used as solvent instead of ethyl acetate with increasing yields. Concerning the protected indazole 4d, it has been determinated by 1H NMR that this product was a mixture of (N-1 and N-2)-THPindazole with a 4da/4db ratio of 3:1 (Scheme 2 and Table 1). In order to establish conditions that enable an efficient and convenient protocol for the formation of indazolylboronic esters and acids in general, our initial focus was on optimizing the synthesis of 5-indazolyl boronic species. During the last decades, alkyl and aryl boronate esters and acids were occasionally prepared by reacting an organometallic intermediate generated from an arene or an aryl halide and stoichiometric quantities of a metalating agent with a boron electrophile.21 Thus, taking into account our know-how in the laboratory about the halogen–metal exchange for the synthesis of various boronic species,22 bromine–lithium exchange and iodine–lithium exchange were carried out (starting from N-SEM indazoles 2c and 2d) in dry THF at –78 °C with n-BuLi or t-BuLi followed by a subsequent quench with triisopropylborate [B(OiPr)3] as electrophile. Unfortunately, only the deshalo products were recovered. In front of our unsuccessful preliminary attempts, we decided to modify our strategy to obtain indazolylboronic esters. In 1995, Miyaura and coworkers reported the synthesis of arylboronates by the palladium-mediated cross-coupling reaction of tetraalkoxydiboron reagents with haloarenes.23 They used bis(pinacolato)diboron as an easily handled source of nucleophilic organoboron reagent, 1,1-bis(diphenylphosphino)ferrocenedichloropalladium–CH2Cl2 [PdCl2(dppf)] as a source of palladium and potassium acetate (KOAc) as base which is recognized to be a suitable weak base for a wide variety of aromatic substrates and enables to achieve

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© Thieme Stuttgart · New York

high yields and purities, in a polar solvent. Furthermore, the resultant pinacolyl boronate esters have the advantage of being stable compounds which can be purified by chromatography. With this in mind and starting from 5-iodoindazole 2d, bis(pinacolato)diboron, PdCl2(dppf), and KOAc, the procedure recently described by Reich and coworkers was applied using DMSO as solvent at 80 °C for two hours (Scheme 3).24 But in our hands, only the byproduct 6 (called dimer)2a resulting of the homocoupling reaction was isolated in a 85% yield (Table 2, entry 1). O

i N

Br / I 2a–f

N

B

N

O

SEM

N SEM

5a–d N

SEM

N

N

SEM

N

6

Scheme 3 Reagents and conditions: i) KOAc (4.6 equiv), PdCl2(dppf)–CH2Cl2 (0.08 equiv), bis(pinacolato)diboron (1.15 equiv), argon, 79–98%. Table 2 Study of the Formation of Protected Indazolylboronic Esters 5a–d Entry

Indazoles 2 Solvent

1

2d

DMSO

2

2d

3

a

Time (min) Yield (%) of 5 or 6 120

6

85

DMSO

15

5b

85

2c

DMSO

15

6

87

4

2c

1,4-dioxaneb

30

5b

67

5

2a

1,4-dioxane

45

5a

98

6

2e

1,4-dioxane

15

5c

98

7

2f

1,4-dioxane

240

5d

79

a

With DMSO as solvent the reactions were performed at 80 °C. With 1,4-dioxane as solvent the reactions were performed under reflux conditions.

b

LETTER R

R i

Br

O

N

R = H, Me

N

B

N

O

N

R'

R'

R' = Ac 3a–c R' = THP 4a–d

R' = Ac 7a–c R' = THP 8a–d

Scheme 4 Reagents and conditions: i) KOAc (4.6 equiv), PdCl2(dppf)–CH2Cl2 (0.08 equiv), bis(pinacolato)diboron (1.15 equiv), argon, 1,4-dioxane, reflux, time, 18–98%. Table 3 8a–d Indazoles

Synthesis of Protected Indazolylboronic Esters 7a–c and Time (h)

Yield (%) of 7 or 8

3a

0.25

7a

98

3b

4

7b

97

3c

24

7c

90a

4a

3

8a

87

4b

3

8b

89

4c

4

8c

77

4d

4

8d

18

a

617

Reactivities in Suzuki–Miyaura Cross-Coupling

Subsequently, with the aim to investigate the reactivity of prepared protected indazole boronic acid pinacolyl esters, two examples of their potential applications are depicted in Scheme 5. Boronates were coupled with 4-iodoanisole or 1-chloro-2-iodobenzene in a standard Suzuki–Miyaura cross-coupling reaction, furnishing a range of arylindazoles 9–17 (Table 4). Our first attempts at 60 °C in DMF with K3PO4 (1 equiv) as base and aryl halide (1.2 equiv) provided the desired compounds in moderate to good yields (25–65%).26 In order to compare other reaction conditions, Cs2CO3 (2 equiv) as base in a mixture 1,4-dioxane–water (2:1) under reflux conditions with Pd(Ph3P)4 (5 mol%) and aryl halide (1.5 equiv) gave similar or better yields (37–73%).27,28 Moreover, the synthesis of hydroxyindazoles from the corresponding boronic esters has been examined. Action of hydrogen peroxide for one hour at room temperature on compounds 5a–d bearing a SEM group did not afford the expected products. But the same conditions applied to the acylated 4- and 5-indazolylboronic esters 7a and 7b provided the corresponding hydroxy compounds 18a and 18b with 98% and 36% yields, respectively, providing an interesting alternative for the synthesis of hydroxyindazoles.29,30 These results

The reaction was performed at 80 °C with DMSO as solvent.

O B

N

Next, reducing the reaction time to 15 minutes (reaction was monitored by TLC) resulted in the formation of desired boronate 5b with a very good yield of 85% without formation of the dimer (Table 2, entry 2). Surprisingly, the same conditions applied to the protected 5-bromoindazole 2c provided exclusively the dimer 6 with 87% yield (Table 2, entry 3). To avoid the formation of this byproduct, the effect of the solvent was examined. Gratifyingly, a high conversion of 2c into the desired boronate 5b (Table 2, entry 4) was obtained when 1,4-dioxane was used as solvent. Furthermore, running the reaction in 1,4dioxane eliminated the formation of the dimer side product 6 and gave the indazolylboronic esters 5a and 5c,d in excellent yields when the corresponding bromoindazoles 2a and 2e,f were used (Table 2, entries 5–7). Finally, the conditions selected for additional studies in position 4, 5, 6, and 7 of the indazole ring with acetyl and THP protecting groups encompassed the use of 1,4-dioxane as solvent under reflux conditions and starting from the bromo derivatives with a control of the reaction times (Scheme 4).25 Similarly, the acetyl-protected indazoles 3a–c were converted into the corresponding boronic esters 7a–c with excellent yields (90–98%). Unfortunately, indazoles 3d,e gave the corresponding unprotected haloindazoles under the same conditions. Next, indazolylboronic esters 8a–c were obtained from the related 1THP-1H-haloindazoles 4a–c with very good yields (77– 89%). However, a moderate yield was obtained for the 7indazolylboronic ester 8d probably due to the hindrance generated by the group THP on the C-7 position of the indazole nucleus (Table 3).

i

N

N

O

Y

N

R

R

9–17 R = SEM, Ac or THP Y = 2-Cl or 4-OMe

O B

ii

N

HO

N

N

O 7a,b

N 18a,b

O

O

Scheme 5 Reagents and conditions: i) Method I: 4-iodoanisole or 1chloro-2-iodobenzene (1.2 equiv), K3PO4 (1 equiv), Pd(Ph3P)4 (0.08 equiv), argon, DMF, 60 °C, 3 h, 25–65%; Method II: 4-iodoanisole (1.5 equiv), Cs2CO3 (2 equiv), Pd(Ph3P)4 (0.05 equiv), argon, 1,4dioxane–water (2:1), reflux, 12 h, 37–73%; ii) H2O2 aq, EtOAc, r.t., 1 h, 36–98%. Table 4

Synthesis of Protected Arylindazoles 9–17

Boronates

Method

Y

5a

I

2-Cl

5b

I

5c

Yield (%) of indazole 9

42

4-MeO

10

65

I

4-MeO

11

25

5d

II

4-MeO

12

37

7a

I

4-MeO

13

40

8a

II

4-MeO

14

50

8b

I

4-MeO

15

34

8c

II

4-MeO

16

64

8d

II

4-MeO

17

73

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LETTER

F. Crestey et al.

demonstrate that construction of new arylindazole as well as hydroxyindazole libraries are feasible. In summary, an efficient and rapid protocol for synthesis of various N-protected indazole boronic acid pinacolyl esters in good to high yields has been developed, providing a promising access to new aryl and hydroxyindazole libraries after subsequent Suzuki–Miyaura cross-coupling or hydroxydeboronation reactions. Considering the important properties of indazole derivatives, this methodology allowing the facile introduction of indazole moiety on various scaffolds could be a great interest for organic chemists to achieve new valuable building blocks for the use in medicinal chemistry as well as diversity-oriented synthesis. Further studies concerning construction of new substituted derivatives are currently in progress.

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Acknowledgment We thank Dr. Christophe Philippo for helpful discussions.

References and Notes (1) (a) Crestey, F.; Stiebing, S.; Legay, R.; Collot, V.; Rault, S. Tetrahedron 2007, 63, 419. (b) Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron Lett. 2000, 41, 9053. (c) Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetrahedron 1999, 55, 6917. (2) (a) Crestey, F.; Collot, V.; Stiebing, S.; Lohier, J.-F.; Sopkova-de Oliveira Santos, J.; Rault, S. Tetrahedron Lett. 2007, 48, 2457. (b) Crestey, F.; Collot, V.; Stiebing, S.; Rault, S. Synthesis 2006, 3506. (c) Crestey, F.; Collot, V.; Stiebing, S.; Rault, S. Tetrahedron 2006, 62, 7772. (d) Witulski, B.; Azcon, J. R.; Alayrac, C.; Arnautu, A.; Collot, V.; Rault, S. Synthesis 2005, 771. (e) Arnautu, A.; Collot, V.; Calvo Ros, J.; Alayrac, C.; Witulski, B.; Rault, S. Tetrahedron Lett. 2002, 43, 2695. (f) Collot, V.; Varlet, D.; Rault, S. Tetrahedron Lett. 2000, 41, 4363. (3) (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019. (b) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933. (c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941. (4) (a) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (5) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117. (6) Salzbrunn, S.; Simon, J.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett 2000, 1485. (7) Thiebes, C.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett 1998, 141. (8) Urawa, Y.; Ogura, K. Tetrahedron Lett. 2002, 44, 271. (9) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463. (10) (a) Hall, D. G. Boronic Acids – Preparation and Applications in Organic Synthesis; Wiley-VCH: Weinheim, 2005. (b) Chincilla, R.; Najera, C.; Yus, M. Chem. Rev. 2004, 104, 2667. (11) For a recent review on heterocyclic boronic acids, see: Tyrell, E.; Brookes, P. Synthesis 2003, 469. (12) For the main references at this time to obtain 4-indazolylboronic acids and esters, see: (a) Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S. T.; Box, G.; Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Eccles, S. A.; Synlett 2009, No. 4, 615–619

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Friedman, L. S.; Hayes, A.; Hancox, T. C.; Kugendradas, A.; Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.; Patel, S.; Pergl-Wilson, G. H.; Raynaud, F. I.; Robson, A.; Saghir, N.; Salphati, L.; Sohal, S.; Ultsch, M. H.; Valenti, M.; Wallweber, H. J. A.; Wan, N. C.; Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. Med. Chem. 2008, 51, 5522. (b) Chuckowree, I.; Folkes, A.; Hancox, T.; Shuttleworth, S. WO 07129161, 2006; Chem. Abstr. 2007, 147, 541901. (c) Shuttleworth, S. J.; Folkes, A. J.; Chuckowree, I. S.; Wan, N. C.; Hancox, T. C.; Baker, S. J.; Sohal, S.; Latif, M. A. WO 06046040, 2006; Chem. Abstr. 2006, 144, 450724. (d) Yoon, T.; Yuan, J.; Lee, K.; Maynard, G. D.; Liu, N. WO 06004589, 2006; Chem. Abstr. 2006, 144, 128985. (e) Lee, K.; Yuan, J.; Maynard, G. D.; Hutchison, A.; Mitchell, S. WO 05110991, 2005; Chem. Abstr. 2005, 144, 6683. For the main references at this time to obtain 5-indazolylboronic acids and esters, see: (a) Alberti, M. J.; Jung, D. K. WO 06044753, 2006; Chem. Abstr. 2006, 144, 432843. (b) Yamashita, D. S.; Lin, H.; Wang, W. WO 05085227, 2005; Chem. Abstr. 2005, 143, 306183. (c) Hagihara, M.; Komori, K.-I.; Sunamoto, H.; Nishida, H.; Matsugi, T.; Nakajima, T.; Hatano, M.; Kido, K.; Hara, H. WO 05035506, 2005; Chem. Abstr. 2005, 142, 411353. (d) McAlpine, I. J.; Deal, J. G.; Johnson, M. C.; Kephart, S. E.; Park, J. Y.; Romines, W. H.; Tikhe, J. G. US 05090529, 2005; Chem. Abstr. 2005, 142, 430272. (e) Shoda, M.; Kuriyama, H. WO 03070686, 2003; Chem. Abstr. 2003, 139, 214465. For the main references at this time to obtain 6-indazolylboronic acids and esters, see: (a) Frazee, J. S.; Hammond, M.; Kano, K.; Manns, S.; Nakamura, H.; Thompson, S. K.; Washburn, D. G. WO 06063167, 2006; Chem. Abstr. 2006, 145, 62865. (b) Lu, T.; Thieu, T. V.; Player, M. R.; Lee, Y.-K.; Parks, D. J.; Markotan, T. P.; Pan, W.; Milkiewicz, K. L. WO 06047415, 2006; Chem. Abstr. 2006, 144, 450703. (c) Bamborough, P.; Campos, S. A.; Patel, V. K.; Swanson, S.; Walker, A. L. WO 05073189, 2005; Chem. Abstr. 2005, 143, 211906. For the main references at this time about 7-indazolylboronic acids and esters, see: (a) Shipps, G. W. Jr.; Cheng, C. C.; Huang, X.; Fischmann, T. O.; Duca, J. S.; Richards, M.; Zeng, H.; Sun, B.; Reddy, P. A.; Wong, T. T.; Tadikonda, P. K.; Siddiqui, M. A.; Labroli, M. M.; Poker, C.; Guzi, T. J. WO 08054702, 2008; Chem. Abstr. 2008, 148, 552346. (b) Kelly, M.; Lee, Y.; Liu, B.; Fujimoto, T.; Freundlich, J.; Dorsey, B. D.; Flynn, G. A.; Husain, A. US 06270686, 2006; Chem. Abstr. 2006, 146, 7835. Boulouard, M.; Schumann-Bard, P.; Butt-Gueulle, S.; Lohou, E.; Stiebing, S.; Collot, V.; Rault, S. Bioorg. Med. Chem. Lett. 2007, 17, 3177. Kania, R. S.; Bender, S. L.; Borchardt, A. J.; Braganza, J. F.; Cripps, S. J.; Hua, Y.; Johnson, M. D.; Johnson, T. O. Jr.; Luu, H. T.; Palmer, C. L.; Reich, S. H.; Tempczyk-Russell, A. M.; Teng, M.; Thomas, C.; Varney, M. D.; Wallace, M. B. WO 0102369, 2001; Chem. Abstr. 2001, 134, 100864. Gérard, A.-L.; Bouillon, A.; Mahatsekake, C.; Collot, V.; Rault, S. Tetrahedron Lett. 2006, 47, 4665. Primas, N.; Mahatsekake, C.; Bouillon, A.; Lancelot, J.-C.; Sopkova-de Oliveira Santos, J.; Lohier, J.-F.; Rault, S. Tetrahedron 2008, 64, 4596. Young, M. B.; Barrow, J. C.; Glass, K. L.; Lundell, G. F.; Newton, C. L.; Pellicore, J. M.; Rittle, K. E.; Selnick, H. G.; Stauffer, K. J.; Vacca, J. P.; Williams, P. D.; Bohn, D.; Clayton, F. C.; Cook, J. J.; Krueger, J. A.; Kuo, L. C.; Lewis, S. D.; Lucas, B. J.; McMasters, D. R.; Miller-Stein, C.;

LETTER

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Pietrak, B. L.; Wallace, A. A.; White, R. B.; Wong, B.; Yan, Y.; Nantermet, P. G. J. Med. Chem. 2004, 47, 2995. For example, see: (a) Jiang, Q.; Ryan, M.; Zhichkin, P. J. Org. Chem. 2007, 72, 6618. (b) Lee, I. Y. C.; Jung, M. H.; Lim, H.-J.; Lee, H. W. Heterocycles 2005, 65, 2505. (c) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org. Chem. 2002, 67, 5176. (d) Schinazi, R. F.; Prusoff, W. H. J. Org. Chem. 1985, 50, 841. (a) Voisin, A.-S.; Bouillon, A.; Lancelot, J.-C.; Rault, S. Tetrahedron 2005, 61, 1417. (b) Bouillon, A.; Lancelot, J.-C.; Sopkova-de Oliveira Santos, J.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2003, 59, 10043; and references cited therein. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. Reich, S. H.; Bleckman, T. M.; Kephart, S. E.; Romines, W. H. III.; Wallace, M. B. WO 01053268, 2001; Chem. Abstr. 2001, 135: 137505. Typical Experimental Procedure for the Synthesis of Indazolylboronic Esters To a solution of 1-(4-bromoindazol-1-yl)ethanone (3a, 1.5 g, 6.3 mmol) in 1,4-dioxane (25 mL) were added successively bis(pinacolato)diboron (1.8 g, 7.2 mmol, 1.15 equiv) and KOAc (2.8 g, 23.8 mmol, 4.6 equiv) at r.t. The reaction mixture was degassed under vacuum with argon replacement three times, then PdCl2 (dppf)–CH2Cl2 (0.3 g, 0.5 mmol, 0.08 equiv) was added, and the degassing procedure was repeated twice. The reaction was heated under reflux conditions for 15 min then concentrated in vacuo. After the addition of EtOAc, the organic layer was washed successively with H2O and brine, dried over MgSO4, and the solvent evaporated in vacuo. The crude material was purified by flash column chromatography on SiO2 (EtOAc– cyclohexane, 1:3) to give 1-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)indazol-1-yl)ethanone (7a); yield 1.8 g (98%); pink solid; mp 128 °C. TLC: Rf = 0.6 (EtOAc– cyclohexane, 1:4). IR (KBr): 2976, 1713, 1601, 1415, 1349, 1325, 1174, 1151, 932, 756 cm–1. 1H NMR (400 MHz,

Reactivities in Suzuki–Miyaura Cross-Coupling

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619

CDCl3): d = 1.42 (s, 12 H), 2.80 (s, 3 H), 7.55 (t, J = 8.3 Hz, 1 H), 7.82 (d, J = 7.1 Hz, 1 ), 8.54 (d, J = 7.1 Hz, 1 H), 8.55 (s, 1 H). 13C NMR (100 MHz, CDCl3): d = 23.1, 25.0, 84.2, 118.3, 128.6, 130.6, 132.0, 138.3, 141.7, 171.1. MS (EI): m/ z (%) = 286 (53) [M+], 244 (100), 243 (39), 229 (14), 158 (70), 145 (34), 144 (68), 134 (67). Anal. Calcd for C15H19BN2O3: C, 62.96; H, 6.69; N, 9.79. Found: C, 62.39; H, 6.48; N, 9.23. For Suzuki–Miyaura cross-coupling reactions using K3PO4 as base in DMF, see: (a) Cailly, T.; Fabis, F.; Rault, S. Tetrahedron 2006, 62, 5862. (b) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207. For Suzuki–Miyaura cross-coupling reactions using Na2CO3 or Cs2CO3 as base in dioxane, see: (a) Song, Y. S.; Lee, Y.-J.; Kim, B. T.; Heo, J.-N. Tetrahedron Lett. 2006, 47, 7427. (b) Heo, Y.; Song, Y. S.; Kim, B. T.; Heo, J.-N. Tetrahedron Lett. 2006, 47, 3091. (c) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 1999, 37, 3387. 7-(4-Methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1Hindazole (17) Yield 0.3 g (73%); white solid. TLC: Rf = 0.1 (EtOAc– cyclohexane, 1:10). IR (KBr): 3428, 2932, 1611, 1497, 1245, 1078, 1032, 824 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.37–1.42 (m, 2 H), 1.76–1.78 (m, 1 H), 1.90–1.95 (m, 1 H), 2.56–2.58 (m, 1 H), 2.91–2.96 (m, 1 H), 3.74–3.80 (m, 1 H), 3.91 (s, 3 H), 4.04–4.07 (m, 1 H), 5.00 (dd, J = 12.7, 2.2 Hz, 1 H), 7.02 (dd, J = 7.3, 1.4 Hz, 2 H), 7.18–7.19 (m, 2 H), 7.23–7.26 (m, 2 H), 7.64–7.70 (m, 1 H), 8.12 (s, 1 H). MS (EI): m/z (%) = 308 (22) [M+], 224 (100), 209 (26), 192 (2), 182 (8), 154 (7), 85 (8). Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 74.30; H, 6.74; N, 9.28. Schumann, P.; Collot, V.; Hommet, Y.; Gsell, W.; Dauphin, F.; Sopkova, J.; McKenzie, E. T.; Duval, D.; Boulouard, M.; Rault, S. Bioorg. Med. Chem. Lett. 2001, 11, 1153. The use of Oxone® (2KHSO5–KHSO4–K2SO4) as oxidative reagent in the presence of Na2CO3 in a mixture of H2O– acetone (1:1) at 0 °C led to the desired compounds but in lower yields.

Synlett 2009, No. 4, 615–619

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